Collagen type XI α1 facilitates head and neck squamous cell cancer growth and invasion.

BACKGROUND: Although it is well established that the extracellular matrix affects tumour progression, not much is known about the various components and their effect on head and neck squamous cell carcinoma (HNSCC) progression. Levels of collagen type XI α1 (colXIα1), a minor fibrillar collagen, have been shown to be increased in tumour compared with normal tissue in several cancers, including colorectal, breast, and non-small cell lung cancer. Currently, the functional significance of colXIα1 is not understood. METHODS: We examined the expression levels of colXIα1 mRNA and elucidated the functional role of colXIα1 in HNSCC. Cell proliferation, invasion, and migration were examined with and without colXIα1 knockdown with siRNA in HNSCC cells. RESULTS: Our data demonstrate that colXIα1 expression is increased in tumour samples compared with levels in normal adjacent tissue in 16/23 HNSCC patients. In addition, colα11 is increased in HNSCC cell lines compared with normal immortalised epithelial cells and is increased in tumour-derived fibroblasts compared with normal fibroblasts. Using an siRNA approach, we demonstrate that colXIα1 contributes to proliferation, migration, and invasion of HNSCC. CONCLUSION: Our cumulative findings suggest that colXIα1 contributes to HNSCC tumorigenesis and may serve as a potential therapeutic target.

Replicative senescence of biliary epithelial cells precedes bile duct loss in chronic liver allograft rejection: increased expression of p21(WAF1/Cip1) as a disease marker and the influence of immunosuppressive drugs.

Early chronic liver allograft rejection (CR) is characterized by distinctive cytological changes in biliary epithelial cells (BECs) that resemble cellular senescence, in vitro, and precede bile duct loss. If patients suffering from early CR are treated aggressively, the clinical and histopathological manifestations of CR can be completely reversed and bile duct loss can be prevented. We first tested whether the senescence-related p21(WAF1/Cip1) protein is increased in BECs during early CR, and whether treatment reversed the expression. The percentage of p21+ BECs and the number of p21+ BECs per portal tract is significantly increased in early CR (26 +/- 17% and 3.6 +/- 3.1) compared to BECs in normal liver allograft biopsies or those with nonspecific changes (1 +/- 1% and 0.1 +/- 0.3; P: < 0.0001 and P: < 0.02), chronic hepatitis C (2 +/- 3% and 0.7 +/- 1; P: < 0.0001 and P: < 0.04) or obstructive cholangiopathy (7 +/- 7% and 0.7 +/- 0.6; P: < 0.006 and P: = 0.04). Successful treatment of early CR is associated with a decrease in the percentage of p21+ BECs and the number of p21+ BECs per portal tract. In vitro, nuclear p21(WAF1/Cip1) expression is increased in large and multinucleated BECs, and is induced by transforming growth factor (TGF)-beta. TGF-beta1 also increases expression of TGF-beta receptor II, causes phosphorylation of SMAD-2 and nuclear translocation of p21(WAF1/Cip1), which inhibits BEC growth. Because conversion from cyclosporine to tacrolimus is an effective treatment for early CR, we next tested whether these two immunosuppressive drugs directly influenced BEC growth in vitro. The results show that cyclosporine, but not tacrolimus, stimulates BEC TGF-beta1 production, which in turn, causes BEC mito-inhibition and up-regulation of nuclear p21(WAF1/Cip1). In conclusion, expression of the senescence-related p21(WAF1/Cip1) protein is increased in BECs during early CR and decreases with successful recovery. Replicative senescence accounts for the characteristic BEC cytological alterations used for the diagnosis of early CR and lack of a proliferative response to injury. The ability of cyclosporine to inhibit the growth of damaged BECs likely accounts for the relative duct sparing properties of tacrolimus.

Further analysis of idiosyncratic antecedent influences during the assessment and treatment of problem behavior.

Recent research findings suggest that idiosyncratic variables can influence the outcomes of functional analyses (E. G. Carr, Yarbrough, & Langdon, 1997). In the present study, we examined idiosyncratic environment-behavior relations more precisely after identifying stimuli (i.e., a particular toy and social interaction) associated with increased levels of problem behavior. Two children, an 8-year-old boy with moderate mental retardation and a 5-year-old boy with no developmental delays, participated. Results of functional analyses for both children indicated that idiosyncratic antecedent stimuli set the occasion for occurrences of problem behavior (hand biting or hand flapping) and that problem behavior persisted in the absence of social contingencies. Further analyses were conducted to identify specific components of the stimuli that occasioned problem behavior. Treatments based on results of the analyses successfully reduced self-injury and hand flapping.

Acute obstructive cholangiopathy in interleukin-6 deficient mice: compensation by leukemia inhibitory factor (LIF) suggests importance of gp-130 signaling in the ductular reaction.

AIM: The hypothesis that interleukin-6-IL-6/gp130 signaling is involved in liver and biliary epithelial cell (BEC) biology and growth control was tested by subjecting homozygous IL-6 deficient mice (IL-6-/-) and wild type (IL-6+/+) littermate controls to bile duct ligation (BDL). MATERIALS AND METHODS: During the first week after BDL, the two groups were compared with respect to routine liver injury tests, liver histology, BEC and hepatocyte DNA synthesis, together with the expression of mRNA and protein of IL-6 as well as related growth factors, and their receptors. RESULTS: During the first week after BDL, there was marked upregulation of IL-6 mRNA and protein in the IL-6+/+ mice only in the vicinity of the biliary tree; whereas, biliary/peri-biliary IL-6R, HGF and met mRNA and protein increased in both groups. IL-6, HGF mRNA and protein localized to periductal inflammatory cells and stellate cells, while met and IL-6R protein were upregulated in the BEC and, to a lesser extent, in hepatocytes. This occurred during maximal proliferation of the BEC. Despite the absence of IL-6 in the IL-6-/- mice, there were only mildly phenotypic differences between the two groups, and no differences in mortality. Compared to IL-6+/+ controls, IL-6-/- mice showed slightly less BEC proliferation, a trend toward more liver injury, and significantly higher total serum bilirubin (TB) levels, suggestive of impaired biliary tree integrity. These changes were associated with slightly less HGF mRNA and protein expression in the IL-6-/- mice, but the differences were not significant. Leukemia inhibitory factor (LIF), another gp-130 ligand, also showed marked peri-biliary upregulation after BDL in both groups, and also induced BEC DNA synthesis, in vitro. CONCLUSIONS: The mild phenotypical differences between IL-6+/+ and IL-6-/- mice in the acute response to BDL is most likely attributable to the redundancy of the gp-130 signaling system. However, the long-term response to BDL results in a distinct phenotype in the IL-6-/- mice, marked by a relentless rise in serum total bilirubin and an inability to maintain compensatory increase in liver mass.

Further evaluation of low-ranked items in stimulus-choice preference assessments.

The generality of the findings reported by DeLeon, Iwata, and Roscoe (1997) was examined by conducting two stimulus-choice preference assessments, the second of which evaluated low-ranked items from the initial assessment. Results for the 2 participants suggested that supplementary assessments of low-ranked items may be useful for identifying a wider variety of reinforcing stimuli.

Variable-time reinforcement schedules in the treatment of socially maintained problem behavior.

Noncontingent reinforcement (NCR) consists of delivering a reinforcer on a time-based schedule, independent of responding. Studies evaluating the effectiveness of NCR as treatment for problem behavior have used fixed-time (FT) schedules of reinforcement. In this study, the efficacy of NCR with variable-time (VT) schedules was evaluated by comparing the effects of VT and FT reinforcement schedules with 2 individuals who engaged in problem behavior maintained by positive reinforcement. Both FT and VT schedules were effective in reducing problem behavior. These findings suggest that VT schedules can be used to treat problem behavior maintained by social consequences.

An evaluation of the properties of attention as reinforcement for destructive and appropriate behavior.

The analogue functional analysis described by Iwata, Dorsey, Slifer, Bauman, and Richman (1982/1994) identifies broad classes of variables (e.g., positive reinforcement) that maintain destructive behavior (Fisher, Ninness, Piazza, & Owen-DeSchryver, 1996). However, it is likely that some types of stimuli may be more effective reinforcers than others. In the current investigation, we identified 2 participants whose destructive behavior was maintained by attention. We used concurrent schedules of reinforcement to evaluate how different types of attention affected both destructive and appropriate behavior. We showed that for 1 participant praise was not an effective reinforcer when verbal reprimands were available; however, praise was an effective reinforcer when verbal reprimands were unavailable. For the 2nd participant, we identified a type of attention that effectively competed with verbal reprimands as reinforcement. We then used the information obtained from the assessments to develop effective treatments to reduce destructive behavior and increase an alternative communicative response.

Reductions in self-injury produced by transcutaneous electrical nerve stimulation.

Transcutaneous electrical nerve stimulation is used to reduce pain but also may be useful for self-injurious behavior (SIB). In the current investigation, a microcurrent electromedical device, classified as a transcutaneous electrical nerve stimulator (TENS), was applied with a man with Down syndrome who displayed SIB that persisted in the absence of social contingencies. Although clinically significant results were not maintained, a clear difference in the rates of SIB during active and inactive TENS was observed.

Evaluating the reinforcing effects of choice in comparison to reinforcement rate.

A concurrent-operants arrangement was used to evaluate a boy's preference for a choice condition (in which he chose the reinforcement) over a no-choice condition (in which the therapist selected the reinforcement for him) when (a) these conditions produced equal rates of reinforcement and (b) lower rates of reinforcement were associated with the choice condition. The boy preferred the choice condition even when it resulted in a much less favorable rate of reinforcement than the no-choice condition (up to 4000% less).

Evaluation of client preference for function-based treatment packages.

Functional communication training (FCT) and noncontingent reinforcement (NCR) are commonly prescribed treatments that are based on the results of a functional analysis. Both treatments involve delivery of the reinforcer that is responsible for the maintenance of destructive behavior. One major difference between the two treatment procedures is that client responding determines reinforcement delivery with FCT (e.g., reinforcement of communication is delivered on a fixed-ratio 1 schedule) but not with NCR (e.g., reinforcement is delivered on a fixed-time 30-s schedule). In the current investigation, FCT and NCR were equally effective in reducing 2 participants' destructive behavior that was sensitive to attention as reinforcement. After the treatment analysis, the participants' relative preference for each treatment was evaluated using a modified concurrent-chains procedure. Both participants demonstrated a preference for the FCT procedure. The results are discussed in terms of treatment efficacy and preference for control over when reinforcement is delivered. In addition, a method is demonstrated in which clients with developmental disabilities can participate in selecting treatments that are designed to reduce their destructive behavior.

The use of positive and negative reinforcement in the treatment of escape-maintained destructive behavior.

We identified 3 clients whose destructive behavior was sensitive to negative reinforcement (break from tasks) and positive reinforcement (access to tangible items, attention, or both). In an instructional context, we then evaluated the effects of reinforcing compliance with one, two, or all of these consequences (a break, tangible items, attention) when destructive behavior produced a break and when it did not (escape extinction). For 2 clients, destructive behavior decreased and compliance increased when compliance produced access to tangible items, even though destructive behavior resulted in a break. For 1 client, extinction was necessary to reduce destructive behavior and to increase compliance. Subsequently, when the schedule of reinforcement for compliance was faded for all clients, destructive behavior was lower and fading proceeded more rapidly when compliance produced multiple functional reinforcers (i.e., a break plus tangible items or attention) and destructive behavior was on extinction. The results are discussed in terms of the effects of relative reinforcement value and extinction on concurrent operants.

Nondirective prompting and noncontingent reinforcement in the treatment of destructive behavior during hygiene routines.

The escape-maintained destructive behavior of a girl with mental retardation persisted during hygiene routines with directive prompting, differential reinforcement for compliance, and extinction as treatment. Using nondirective prompting and noncontingent reinforcement, destructive behavior was reduced to near-zero levels during the hygiene routine.